Inefficient Placental Virus Replication and Absence of Neonatal Cell-Specific Immunity Upon Sars-CoV-2 Infection During Pregnancy

Abstract

Pregnant women have been carefully observed during the COVID-19 pandemic, as the pregnancy-specific immune adaptation is known to increase the risk for infections. Recent evidence indicates that even though most pregnant have a mild or asymptomatic course, a severe course of COVID-19 and a higher risk of progression to diseases have also been described, along with a heightened risk for pregnancy complications. Yet, vertical transmission of the virus is rare and the possibility of placental SARS-CoV-2 infection as a prerequisite for vertical transmission requires further studies. We here assessed the severity of COVID-19 and onset of neonatal infections in an observational study of women infected with SARS-CoV-2 during pregnancy. Our placental analyses showed a paucity of SARS-CoV-2 viral expression ex vivo in term placentae under acute infection. No viral placental expression was detectable in convalescent pregnant women. Inoculation of placental explants generated from placentas of non-infected women at birth with SARS-CoV-2 in vitro revealed inefficient SARS-CoV-2 replication in different types of placental tissues, which provides a rationale for the low ex vivo viral expression. We further detected specific SARS-CoV-2 T cell responses in pregnant women within a few days upon infection, which was undetectable in cord blood. Our present findings confirm that vertical transmission of SARS-CoV-2 is rare, likely due to the inefficient virus replication in placental tissues. Despite the predominantly benign course of infection in most mothers and negligible risk of vertical transmission, continuous vigilance on the consequences of COVID-19 during pregnancy is required, since the maternal immune activation in response to the SARS-CoV2 infection may have long-term consequences for children’s health.

COVID‐19 and vertical transmission: assessing the expression of ACE2/TMPRSS2 in the human fetus and placenta to assess the risk of SARS‐CoV‐2 infection

“…Haematogenous spread as a mechanism of infection and transmission across the placenta into the fetal circulation appears unlikely, due to inefficient viral replication in placental tissues. 25 The fetal intestine, directly exposed to the amniotic fluid via fetal swallowing, shows an increase in the expression of ACE2 throughout gestation with a high level of TMPRSS2 expression in the mucosa. Results from publicly available fetal single cell atlas data support our findings, 22 allowing extension of these observations to 8 PCW, before the gestational age that fetal swallowing is known to begin.…”

COVID-19 in pregnancy: implications for fetal brain development

“…Population-level data suggest that rates of SARS-CoV-2 positivity among newborns in SARS-CoV-2-exposed pregnancies range from 1% to 3% [83,[120][121][122][123][124], with placental infection being a relatively rare event. One meta-analysis of case reports and case series estimated the rate of placental infection as 7% [125], although prospective studies have identified even lower rates of placental infection [83,84,126,127]. Protective mechanisms against placental infection include low rates of maternal SARS-CoV-2 viremia, preserved immune defenses at the syncytiotrophoblast border, and the lack of coordinated expression of molecules required for SARS-CoV-2 attachment and entry (ACE2 and TMPRSS2) into the syncytiotrophoblast [80,83,128].…”

Developmental Aspects of SARS-CoV-2, Potential Role of Exosomes and Their Impact on the Human Transcriptome

“…There seem to be two potential hypotheses of exosomal contribution in utero, as well as in fetal development: (1) SARS-CoV-2 infections via exosomes, or (2) in utero development of immunity. While exosomes have been found to carry viral RNA, there seems to be little to no viral replication in utero [60]. This observation discards the first hypothesis that exosomes may induce viral infection in utero.…”

“…While only ~10% infants were found to be positive for COVID-19, most studied infant cases had developed immunoglobulin G and M (IgG, IgM) antibodies against SARS-CoV-2 [59]. In another study, no viral RNA was detected in the placentas of COVID-19 positive pregnant women [60]. Furthermore, there seems to be no confirmed cases of intrauterine infection of SARS-CoV-2 from mothers to their fetuses.…”

“…Although severe illness has been seen in infants younger than 1 year, such cases have had confirmed underlying comorbidities [61]. These findings suggest that vertical infection is rare, and a natural passive immunity is developed in infants who are born to mothers with COVID-19 [59,60].…”